Discovery of morpholine-based aryl sulfonamides as Na v 1.7 inhibitors

Abstract Replacement of the piperidine ring in the lead benzenesulfonamide Na v 1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Na v 1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Na v 1.7 inhibitors. This report describes the synthesis and SAR of these analogs.